Friedman Constantin S, O'Donnell Marie Anne, Legarda-Addison Diana, Ng Aylwin, Cárdenas Washington B, Yount Jacob S, Moran Thomas M, Basler Christopher F, Komuro Akihiko, Horvath Curt M, Xavier Ramnik, Ting Adrian T
Immunology Institute, Mount Sinai School of Medicine, Box 1630, One Gustave L Levy Place, New York, New York 10029, USA.
EMBO Rep. 2008 Sep;9(9):930-6. doi: 10.1038/embor.2008.136. Epub 2008 Jul 18.
On detecting viral RNAs, the RNA helicase retinoic acid-inducible gene I (RIG-I) activates the interferon regulatory factor 3 (IRF3) signalling pathway to induce type I interferon (IFN) gene transcription. How this antiviral signalling pathway might be negatively regulated is poorly understood. Microarray and bioinformatic analysis indicated that the expression of RIG-I and that of the tumour suppressor CYLD (cylindromatosis), a deubiquitinating enzyme that removes Lys 63-linked polyubiquitin chains, are closely correlated, suggesting a functional association between the two molecules. Ectopic expression of CYLD inhibits the IRF3 signalling pathway and IFN production triggered by RIG-I; conversely, CYLD knockdown enhances the response. CYLD removes polyubiquitin chains from RIG-I as well as from TANK binding kinase 1 (TBK1), the kinase that phosphorylates IRF3, coincident with an inhibition of the IRF3 signalling pathway. Furthermore, CYLD protein level is reduced in the presence of tumour necrosis factor and viral infection, concomitant with enhanced IFN production. These findings show that CYLD is a negative regulator of RIG-I-mediated innate antiviral response.
在检测到病毒RNA时，RNA解旋酶视黄酸诱导基因I（RIG-I）会激活干扰素调节因子3（IRF3）信号通路，以诱导I型干扰素（IFN）基因转录。目前对这种抗病毒信号通路如何受到负调控知之甚少。微阵列和生物信息学分析表明，RIG-I的表达与肿瘤抑制因子CYLD（圆柱瘤病）的表达密切相关，CYLD是一种能去除赖氨酸63连接的多聚泛素链的去泛素化酶，这表明这两种分子之间存在功能关联。CYLD的异位表达会抑制由RIG-I触发的IRF3信号通路和IFN产生；相反，敲低CYLD会增强反应。CYLD会从RIG-I以及TANK结合激酶1（TBK1，一种使IRF3磷酸化的激酶）上去除多聚泛素链，同时抑制IRF3信号通路。此外，在肿瘤坏死因子存在和病毒感染的情况下，CYLD蛋白水平会降低，同时IFN产生增加。这些发现表明CYLD是RIG-I介导的先天性抗病毒反应的负调节因子。
